Hepatitis B virus (HBV) infects the liver of hominoidae, including humans, and causes an inflammation called hepatitis. It is a DNA virus and one of many unrelated viruses that cause viral hepatitis. HBV currently infects at least 350 million people worldwide. 75% of chronically infected HBV patients are living in Asia but the virus has a world-wide diffusion. For example, in the United States, approximately 1.5 million Americans, or about 0.5% of the population have HBV. The infection is especially more common in certain risk groups like men who have sex with other men, renal dialysis patients and persons with haemophilia. Chronic HBV infections affects 10 to 15% of first generation Asian Americans and approximately 5% of children adopted from Russia, Asia and Eastern Europe have chronic HBV infections. Chronic HBV infections may eventually lead to liver cirrhosis and Hepatocellular carcinoma (HCC), a fatal disease with very poor response to current chemotherapy.
Currently available methods of treatment for this global large reservoir of chronically infected subjects are challenging as existing drugs suppress but do not eliminate HBV. Though majority of HBV infected patients respond to currently available methods of treatment showing improvements in liver histology and serum Alanine transaminase (ALT) levels, almost all patients relapse when treatment is stopped. Furthermore, the more common methods of treatment of HBV involve the use of drugs such as lamivudine and adefovir. These drugs however, result in development of anti-viral resistance in the patients, which occur in approximately 20% of patients treated with lamivudine and in about 3% of those treated with adefovir each year. Ultimately a large proportion of patients would develop resistance, at which point, the anti-viral drugs would have little effect.
There is thus a global need for an effective method of anti-viral therapy that results in an HBV specific immune response to efficiently and successfully eliminate the covalently closed circular form of HBV in a patient. Naturally occurring HBV-epitope specific T cells found in some subjects, lead to the subjects having an efficient and innate control of the HBV infection. Past studies have shown that patients with persistent/chronic HBV infection have their HBV-epitope specific T cells deleted or functionally altered. Therefore, increased knowledge of virus-host interactions during HBV infection has prompted speculation that therapeutic restoration of the defective anti-viral immunity present in patients with chronic infection could possibly lead to disease resolution. The validity of this concept was directly demonstrated in patients with chronic HBV infection who underwent bone marrow transplantation and received marrows from donors with natural immunity to HBV. Infusion of a healthy HBV-primed immune system led to resolution of chronic HBV infection in these patients. However, bone marrow transplantation is clearly not an easy therapeutic option for chronically HBV infected patients and attempts to boost HBV-specific immunity using various vaccines in patients with chronic hepatitis B have been disappointing.
A potential cause of failure of the therapeutic vaccine strategy is the fact that the immune system of HBV chronic carriers does not have the same efficiency and repertoire of specificities as that of healthy non-HBV infected subjects. Further, persistent high production of viral antigens in chronic HBV infected patients can delete or tolerize antigen-specific T cells. Chronic HBV infected patients are thus characterized by low/absent HBV-specific CD4+ and CD8+ T cell responses. Moreover, it has been speculated that both low T cell avidity and an ineffective cytokine profile generated in response to HBV infection may contribute to the development of chronic HBV infection rather than viral clearance.
Clearly, more effective therapies targeting molecules involved in the cytokine profile of HBV infected patients are necessary in order to reduce the worldwide morbidity and mortality from HBV infection and HBV-related malignancies.